Leukocytes, and especially polymorphonuclear (PMN) leukocytes, circulate in the blood and do not adhere to the endothelium (the cells lining the vessels). Upon the introduction of an infectious agent, fragments that result from the death of an infectious agent, or another inflammatory substance into nearby tissues, leukocytes, especially PMN, are induced to bind to the endothelium and then migrate into the tissues. Since PMN can recognize and kill many infectious agents, this is a protective mechanism. However, in many disease circumstances, such as sepsis and trauma, PMN react in an exaggerated and deleterious fashion. They may bind so avidly to endothelium as to occlude blood flow. Once in the tissues, they secrete proteases, reactive oxygen intermediates, and other toxic molecules which not only kill infectious agents, but also can result in extensive tissue damage. In addition, they release inflammatory mediators that alter vascular tone and permeability, and that recruit additional leukocytes to the site, thus perpetuating inflammation.
Two diseases in which PMN-mediated damage contributes to morbidity and mortality are endotoxic shock and adult respiratory distress syndrome. In both instances, the lung is a preferred organ for emigration of PMN, and lung damage can be severe enough to cause death.
Adult respiratory distress syndrome (ARDS) can result from both infectious and non-infectious causes; either results in similar pathology as a consequence of PMN emigration. In endotoxic shock associated with infection, the use of antibiotics magnifies the deleterious effects of inflammation. This is due to the mechanism by which such agents exert their anti-infective effects. For example, following the administration of a betalactam antibiotic (or other cell-wall directed antibiotic), the bacteria disintegrate due to lysis by the anti-infective agents. The resulting fragments of bacteria initiate a dramatically enhanced inflammatory response. See Tuomanen et al., Am. Rev. Resoir. Dis., 135, 869-874 (1987). Earlier research has indicated that inhibition of this antibiotic-induced inflammation correlates with improved morbidity and mortality in the setting of meningitis, Tuomanen et al., J. Infect. Dis., 155, 985-990 (1985) and Kadurugamuwa, Program and Abstracts of the 27th ICAA Meeting, p. 205 (1987). In pneumococcal meningitis, for instance, mortality can be directly correlated with the amount of meningeal inflammation, McAllister et al., J. Infect. Dis. 132, 355-360 (1975). Thus, a method of dampening inflammation during the course of therapy with an antibiotic would be advantageous in treating infections, particularly endotoxic shock and ARDS associated with infection.
In a similar fashion, a method of dampening the inflammation associated with ARDS of noninfectious origin would likewise be a useful therapeutic tool for physicians.
A molecule on the surface of PMN that mediates adhesion to endothelium has recently been defined. That molecule, CD18, is thought to mediate adhesion because (a) monoclonal antibodies against CD18 inhibit binding of PMN to endothelium in vitro, (b) injection of monoclonal antibodies against CD18 into rabbits prevents normal emigration of PMN in response to an inflammatory stimulus, (c) PMN from patients with a genetic defect in the expression of CD18 fail to bind to endothelial cells in vitro, and (d) the deficient patients fail to recruit PMN to sites of infection.
CD18 has been previously described as a receptor for the third component of complement, C3bi (Wright et al., PNAS, 80, 5699-5703 (1983). A single receptor thus functions in two capacities, i.e., to mediate the binding of polymorphonuclear leukocytes (PMN) to endothelial cells, and to C3bi-coated cells.
It is thus an object of the present invention to provide a method of inhibiting the influx of leukocytes and particularly polymorphonuclear (PMN) leukocytes into the lung and other organs during sepsis or other infectious or non-infectious trauma which comprises the administration of a therapeutic amount of an anti-CD18 monoclonal antibody or active fragment thereof to a patient in need of such therapy.
It is a further object of this invention to treat inflammation in the lung and other organs in patients having an inflammation caused by sepsis or other infectious or non-infectious trauma by administration of a therapeutic amount of an anti-CD18 monoclonal antibody or active fragment thereof, to a patient in need of such therapy.
Another object of the present invention is to afford a method of treating a patient afflicted with endotoxic shock or adult respiratory distress syndrome by administering a therapeutic amount of an anti-CD18 monoclonal antibody, whereby the amount of the influx of PMN into the lung is eliminated or greatly reduced.
It is a still further object of this invention to eliminate or reduce the influx of leukocytes, and particularly polymorphonuclear (PMN) leukocytes, into the lung and other organs of a patient wherein the patient is being administered an anti-infective agent for an infectious disease by administering a therapeutic amount of an anti-CD18 monoclonal antibody or an active fragment thereof prior to, concurrent with, or after, the administration of the anti-infective agent, thereby eliminating or reducing inflammation.